Diabetes mellitus is associated with aggravated development of vascular complications. Yet, it has not been established whether platelet hyperreactivity contributes as a pathogenetic factor. In order to study the role of activated platelets in diabetes mellitus, we investigated the expression of the membrane activation markers CD63 (GP53) and CD62 (GMP-140) as direct indicators of in vivo activation. The CD63-positive fraction was significantly higher in patients (6.1% X 3.7 +/- 1) than in controls (2.7% X 3 +/- 1). In parallel, the CD62-positive fraction was significantly elevated in patients to 5% X 2.5 +/- 1 in comparison to controls (3% X 2 +/- 1). Patients with angiopathy had a mean increase of 304% in CD63-positive and of 223% in CD62-positive platelets. Patients without clinically detectable angiopathy showed a trend to an increased fraction in CD63-/CD62-positive platelets. There was no correlation of the activation markers with fasting blood glucose, HbA1 or platelet count. CD63 platelet bound fluorescence significantly increased with platelet size in the patient group. We conclude that in diabetes mellitus an increased number of large platelets circulate in an activated state predominantly in patients with angiopathy. This could imply that platelets become activated by vascular lesions. The trend in patients without vascular disease, however, suggests that activated platelets may also basically contribute to the prethrombotic state in diabetes mellitus.

Diabetic neuropathy represents a major health problem, as it is responsible for substantial morbidity, increased mortality, and impaired quality of life. Near-normoglycaemia is now generally accepted as the primary approach to prevention of diabetic neuropathy, but is not achievable in a considerable number of patients. In the past two decades several medical treatments that exert their effects despite hyperglycaemia have been derived from the experimental pathogenetic concepts of diabetic neuropathy. Such compounds have been designed to improve or slow the progression of the neuropathic process and are being evaluated in clinical trials, but with the exception of alpha-lipoic acid (thioctic acid) which is available in Germany, none of these drugs is currently available in clinical practice. Here we review the current evidence from the clinical trials that assessed the therapeutic efficacy and safety of thioctic acid in diabetic polyneuropathy. Thus far, 15 clinical trials have been completed using different study designs, durations of treatment, doses, sample sizes, and patient populations. Within this variety of clinical trials, those with beneficial effects of thioctic acid on either neuropathic symptoms and deficits due to polyneuropathy or reduced heart rate variability resulting from cardiac autonomic neuropathy used doses of at least 600 mg per day. The following conclusions can be drawn from the recent controlled clinical trials. 1.) Short-term treatment for 3 weeks using 600 mg of thioctic acid i.v. per day appears to reduce the chief symptoms of diabetic polyneuropathy. A 3-week pilot study of 1800 mg per day given orally indicates that the therapeutic effect may be independent of the route of administration, but this needs to be confirmed in a larger sample size. 2.) The effect on symptoms is accompanied by an improvement of neuropathic deficits. 3.) Oral treatment for 4-7 months tends to reduce neuropathic deficits and improves cardiac autonomic neuropathy. 4.) Preliminary data over 2 years indicate possible long-term improvement in motor and sensory nerve conduction in the lower limbs. 5.) Clinical and postmarketing surveillance studies have revealed a highly favourable safety profile of the drug. Based on these findings, a pivotal long-term multicenter trial of oral treatment with thioctic acid (NATHAN I Study) is being conducted in North America and Europe aimed at slowing the progression of diabetic polyneuropathy using a clinically meaningful and reliable primary outcome measure that combines clinical and neurophysiological assessment.

and 2 see Acknowledgements for complete list of participating hospitals and clinicsObjectives: Repeatability of a dietary method is important in determining the quality of nutritional data. It should be assessed in the population of interest. This study evaluated the repeatability of nutritional data from standardized three-day dietary records, from the clinic-based, cross-sectional multi-centre EURODIAB IDDM Complications Study. Design and Subjects: 15% of the total EURODIAB cohort was randomly selected to test the repeatability of nutritional intake data. Two three-day records, completed three weeks apart, were available for 216 diabetic patients (7.5%) representative of the total cohort. All records were analysed centrally, for intakes of protein (animal and vegetable), fat (saturated fat and cholesterol), carbohydrate, ®bre, alcohol and energy. Repeatability was measured comparing mean intakes, determining the proportion of patients classi®ed into the same/opposite quartile by the two three-day records and assessing mean differences with standard deviations (s.d. d ).Results There were no signi®cant differences in mean energy and nutrient intakes between the ®rst and second records. Classi®cation of individuals into the opposite quartile occurred only in 0±4% of patients and overall about 50% (range 44±74%) of the subjects were classi®ed into the same quartiles of intakes. Only small mean differences were found for energy intake (7156 (1633) kJ; 95% con®dence limits 7375, 63 kJ) and nutrients with s.d. d s comparable to intra-individual variations in the general population. The differences in energy intake were randomly distributed over the range of intakes. Conclusions: The present study demonstrates that standardized three day dietary records show a high degree of repeatability within a short period of time in a sample of European IDDM patients. The good repeatability strengthens the conclusions drawn from the nutritional data in the EURODIAB IDDM Complications Study.

Kidney disease is a common and costly complication [1,2] of diabetes mellitus, with individuals often requiring dialysis or renal transplantation. More than 30 % of people with insulin-dependent diabetes mellitus (IDDM) are at risk of manifest renal disease [3][4][5]. In the EURODIAB IDDM Complications Study 30.6 % of a stratified European sample of individuals with IDDM aged 15-60 years (mean diabetes duration: 15 years) had albumin excretion rates (AER) of 20 m g/min or higher. In persons with a diabetes duration of 1-5 years the rate of elevated AER was 19.3 % [6]. This high prevalence of micro-and macroalbuminuria even early in IDDM and its predictive association for both clinical nephropathy [7][8][9][10][11][12] and increased cardiovascular disease risk [6,[13][14][15] highlight the potential for early detection and effective prevention of diabetic vascular complications.The use of low protein diets has been shown to reduce the progression of nephropathy in patients with clinically overt diabetic nephropathy [16][17][18][19]. In Diabetologia (1997) Summary For people with insulin-dependent diabetes mellitus (IDDM) renal disease represents a lifethreatening and costly complication. The EURODI-AB IDDM Complications Study, a cross-sectional, clinic-based study, was designed to determine the prevalence of renal complications and putative risk factors in stratified samples of European individuals with IDDM. The present study examined the relationship between dietary protein intake and urinary albumin excretion rate (AER). Food intake was assessed centrally by a standardized 3-day dietary record. Urinary AER was determined in a central laboratory from a timed 24-h urine collection. Complete data were available from 2696 persons with IDDM from 30 centres in 16 European countries. In individuals who reported protein consumption less than 20 % of total food energy intake, mean AER was below 20 m g/min. In those in whom protein intake constituted more than 20 %, mean AER increased, a trend particularly pronounced in individuals with hypertension and/or poor metabolic control. Trends reached statistical significance for intakes of total protein (% of energy, p = 0.01) and animal protein (% of energy, p = 0.02), while no association was seen for vegetable protein (p = 0.83). These findings support the current recommendation for people with diabetes not to exceed a protein intake of 20 % of total energy. Monitoring and adjustment of dietary protein appears particularly desirable for individuals with AER exceeding 20 m g/min (approximately 30 mg/24 h), especially when arterial pressure is raised and/or diabetic control is poor. [Diabetologia (1997[Diabetologia ( ) 40: 1219[Diabetologia ( -1226

Occlusive vascular diseases are promoted by a “prethrombotic state” with increased platelet activity. Polymerization of cytoskeletal proteins and exposure of subcellular structures or rebinding of secreted proteins have been characterized as early reactions after platelet activation preceding adhesion and aggregation. Here, we demonstrate the kinetic increase in specific binding of monoclonal antibodies to thrombospondin (P10) and to platelet membrane activation markers CD63 (GP53, a 53 kD lysosomal protein) and CD62 (GMP140, a 140 kD alpha granule protein) by using a flow‐cytometric bio‐assay and the related change in the actin status by using the DNase‐I inhibition assay after stimulation of normal human platelets with 0.2 U/ml thrombin. F‐actin was raised from 41% to 51% of total platelet actin content 30 s after stimulation and remained thereafter constant (50% at 60 s). Simultaneously, the percentage of P10, CD63, and CD62 positive platelets was elevated from 5.4%, 24.4%, and 9.1% to 67.4%, 80.2%, and 82.3% respectively. The mean number of P10, CD63, and CD62 antibody binding sites increased from 3,300, 1,715, and 2,146 to 6,400, 6,800, and 9,016 per platelet. Conclusively, changes in the organization of the cytoskeletal protein “actin” and exposure of subcellular structures indicating platelet secretion can be regarded as markers of early platelet activation. Thus, the parallel response in both analytical systems provides further support for the diagnostic concept of flow‐cytometric detection of preactivated platelets in the peripheral blood by using fluochrome staining procedures detecting activation dependent structural alterations directly at the cellular level.